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Kappa Delta Young Investigator Focuses on Tendon Healing, Remodeling

Award recognizes efforts of Nelly Andarawis-Puri, PhD

Nelly
Andarawis-Puri, PhD

The winner of the 2018 Kappa Delta Young Investigator
award, Nelly Andarawis-Puri, PhD, discovered biomechanical engineering as an
undergraduate student at Columbia University. She went on to obtain her
doctorate in bioengineering from the University of Pennsylvania and then a
postdoctoral fellowship in orthopaedics at the Icahn School of Medicine at
Mount Sinai. There, she worked with her postdoc mentor and coauthor, Evan L.
Flatow, MD, studying the biologic and structural changes associated with onset
of subrupture tendon damage using the in vino tendon fatigue rat model.

“My work in tendon research spans both basic science and
translational applications,” she explained. As a predoctoral trainee at the
University of Pennsylvania, working with Louis J. Soslowsky, PhD, she focused
on the biomechanics of joint and tendon function, in particular the tendons of
the shoulder.

After establishing that even a small injury to the
supraspinatus tendon led to altered mechanics in the other healthy rotator cuff
tendons, Dr. Andarawis-Puri realized the importance of early interventions for
the health of the joint and not just the injured tendon. “Data from human
cadaveric shoulders showed that the mechanical environment of the intact
infraspinatus tendon is altered in association with injury to the supraspinatus
tendon,” she wrote. Thus, small tears, such as those managed without surgery,
could still lead to devastating changes in the remaining joint.

Motivated by her predoctoral and postdoctoral training, Dr.
Andarawis-Puri adopted a multidisciplinary approach to determine the structural
and regulatory role of the tendon extracellular matrix in the pathogenesis of
tendinopathy and impaired healing of ruptured tendons. Her research
incorporates biomechanics, biology, imaging, and mathematical modeling to
elucidate the mechanisms of damage accumulation that underlie the pathogenesis
of tendinopathy as well as the mechanisms that underlie effective scarless
tendon healing.

The impact of
fatigue

Dr. Andarawis-Puri’s research into the onset and
pathogenesis of tendinopathy showed that fatigue-damage injuries do not
innately remodel or repair. “Fatigue-damaged tendons attempt to repair induced
damage but their ability to remodel is diminished after a certain threshold of
damage is surpassed,” she wrote.

As a result, tendon injuries are often chronic, resulting
from cumulative microtraumas and degeneration that ultimately lead to tendon
failure. Using mouse and rat model, Dr. Andarawis-Puri investigated the
temporal in vivo effects of subrupture fatigue injury. In addition, she studied
the impact of fatigue damage on tendon healing and evaluated the effectiveness
of various therapeutic modalities in improving healing. Finally, she
investigated the effect of exercise and immobilization after tendon repair.

Her studies led to the following conclusions:

Damage begins to accumulate even from just one bout of
sub-rupture fatigue loading.

Induced subrupture damage does not remodel and predisposes
the tendon to further injury.

An increase in the severity of the initial induced damage correlates
with a diminished repair attempt by the tendon.

The timing of exercise initiation after a fatigue injury
will determine whether the exercise leads to repair or further degeneration of
fatigue-damaged tendons (Fig. 1).

Exercise-led remodeling of fatigue-damaged tendons is
associated with decreased apoptosis and an increase in the population of
myofibroblasts.

Exercise can have a protective effect, but data are needed to
guide timing and duration.

Fig. 1 Damage area
fraction (DAF) for exercise-led remodeling and degeneration. Initiation of
exercise one day after fatigue loading led to an increase in DAF. Initiation of
exercise 14 days after fatigue loading led to a decrease in DAF. Modified from
Bell and Boniello et al.

Courtesy of Bell R,
Boniello MRR, Gendron NRR, et al

Based on the data she developed, Dr. Andarawis-Puri
identified several mechanisms by which exercise could lead to remodeling,
thereby opening avenues for diagnostics to help guide the timing of therapeutic
exercises. According to Dr. Andarawis-Puri, “Physiologic loading, such as
exercise, is a powerful modulator of the biological response of tissues.” The
results of her studies showed that delayed initiation of exercise after onset of
fatigue injury leads to structural remodeling. She has also shown that exercise
reduces apoptosis and aggrecan production in fatigue-damaged tendons.

Scarless healing

Because ruptured tendons do not effectively heal due to
the substitution of scar tissue for healthy tendon tissue, Dr. Andarawis-Puri
investigated regenerative models that resulted in scarless tendon healing.
Using adult Murphy Roths Large (MRL/MpJ) mice, which exhibit a regenerative
capacity, she is investigating mechanisms that underlie adult regenerative
healing.

“Shared characteristics between tissues that regenerate
in MRL/MpJ mice suggest that the improved healing ability of these mice is
either systemic or due to biological mechanisms that are common between
tissues,” she wrote. “In contrast, the limitation of MRL/MpJ mice to regenerate
all tissues supports that their regenerative ability is driven by the specific
characteristics of the healing tissue.

“Although effective healing in MRL/MpJ is likely the
result of cooperative roles between the systemic environment and the
environment of the local tissue, we expect that the local tissue environment is
integral to driving regeneration,” she continued. A series of studies generated
the following lessons:

Scarless tendon healing is associated with early increased
cell activity.

The biologic response healing response of regenerative
tendons does not correlate with systemic levels of key inflammatory cytokines.

“Contrary to the prevailing hypotheses of systemically
driven tissue regeneration in MRL/MpJ, our data provide strong evidence to
support further investigation of the role of the local tissue environment in
driving regenerative healing,” she concluded.

Dr. Andarawis-Puri to present later in the week

Dr. Andarawis-Puri will
receive the award during today’s Your Academy 2018 event and will present her
award-winning paper, “Promoting Effective Tendon Healing and Remodeling” during
the 2018 Annual Meeting of the Orthopaedic Research Society, on Sunday at the
Hyatt Regency New Orleans.